How nerves find their targets: Fishing for survival signals

photo credit
In 1949, Rita Levi-Montalcini noticed something unexpected. Her colleague Elmer Bueker had found that nerves would invade tumors that he had implanted into chick embryos. What attracted the nerves to tumors? Indeed, how did nerves ever find their normal targets? Levi-Montalcini noticed that the nerves would also invade tissues near the implanted tumors–suggesting that tumors might be releasing a diffusible nerve growth factor, a postulated substance that could guide either nerve differentiation, growth or survival. Levi-Montalcini proved the existence of a nerve growth factor by culturing just tumors and ganglia in the same dish, finding that the nerves from the ganglia would connect to tumors even outside of embryos. Later, she purified the key protein, now called Nerve Growth Factor (NGF). NGF told us that the way nerves find their targets is unexpectedly adaptive–nerves grow just about everywhere, and they die off if they fail to find targets. 
A short review: Aloe, L. (2004) Rita Levi-Montalcini: the discovery of nerve growth factor and modern neurobiology. Trends Cell Biol 14:395-9. 

Some amazing historical background: An excerpt about her pre-NGF work done in makeshift home labs she set up hiding out in the hills during WWII, from her autobiography, In Praise of Imperfection. Open the excerpt in the right pdf viewer and you'll see some helpful notes in red.

How the genetic code was cracked

some possible 3-letter codes
The structure of DNA, solved in 1953, set off a race to crack the genetic code. How do sequences of 4 nucleotides code for sequences of 20 amino acids? This coding problem lies at the heart of molecular biology. Physicist George Gamow of Big Bang fame contributed the first guess: Spaces between neighboring nucleotides might fit individual amino acids, directly templating protein assembly on the DNA. In Gamow's solution, each nucleotide must contribute to defining two amino acids–an overlapping code. The numerology looked good (there were exactly 20 possible combinations), but Gamow's solution turned out to be wrong: In 1957, Sydney Brenner devised a simple test that disproved this and all overlapping triplet codes. The true code was soon cracked based on beautiful frameshift experiments by Crick et al., and by analysis of proteins synthesized from artificial RNAs.
Supplements: Gamow's guess, Brenner disproves Gamow and all overlapping triplet codes, the decisive artificial RNA experiments

The random origin of mutations versus directed mutations

Luria & Delbrück in 1941.
Original repository:
Cold Spring Harbor Laboratory Archives
Do mutations arise randomly with respect to their fitness effects (undirected mutations), or do organisms acquire mutations that are favorable upon exposure to a new environment (directed mutations)? Most of our current knowledge of evolution and genetics relies on undirected origin of mutations. The Central Dogma, as we know it now, wouldn’t exist if mutations were directed. The question remained largely unanswered until 1943, until Salvador Luria and Max Delbrück conducted an experiment, which, along with their subsequent work, won them the Nobel prize in 1969. This was before DNA was identified as the carrier of genetic information, and we still didn’t know whether prokaryotes and eukaryotes used the same genetic material. The experiment was a brilliant integration of simple microbiology, probability theory and a phylogenetic context. Surprisingly, the experiment used little more technology beyond plating out E. coli with a bacteriophage and counting how often resistant bacterial mutants arose.
 A "recent" review by Lenski & Mittler about the reignited directed mutation controversy. Gives a good summary of the Luria-Delbrück experiment too. -,%20Science,%20Lenski%20&%20Mittler.pdf

Why do we sleep?

Xie et al, 2013.
The question of why animals sleep is one that has gone unanswered for many years. However, new findings have shed light on a possible evolutionary reason for the restorative function of sleep. Using in vivo imaging techniques, researchers at the University of Rochester have found that during sleep the cerebrospinal fluid interchanges with the interstitial fluid of the brain. It then circulates throughout the brain to remove metabolic waste products that form due to neuronal activity. Neurons are especially sensitive to their environment and removal of waste products is thought to prevent cellular damage. One such product, β-amyloid, negatively affects synaptic transmission, and its accumulation is thought to be associated with Alzheimer’s disease. This study showed that during sleep β-amyloid is removed from the brain significantly faster than during waking hours. The findings of this paper are likely to impact sleep and disease research for years to come.
The role of amyloid β in the pathogenesis of Alzheimer's disease.

DNA vs. Protein: who carries the genetic information?

Photo credit
Even though DNA was discovered in 1869, most scientists assumed that proteins carried heritable information. The Avery-MacLeod-McCarty experiment (1944) suggested that DNA was the genetic material, but the general scientific community hesitated to accept this. DNA was thought to be far too simple to contain the complex nature of inheritance, while proteins were thought to be complex enough to carry the genetic information. It wasn’t until the results of the elegantly-designed experiment conducted by Alfred Hershey and Martha Chase were published in 1952 that everyone had to acknowledge that DNA was the hereditary molecule. This experiment was so simple and elegant that no one could argue with the straightforward conclusion.
Avery-MacLeod-McCarty paper that set the stage

Guppies are kind of a big deal: Experimental tests of evolution in the lab and field
In evolutionary biology, we often have to let nature do our experiments for us because evolution is thought to act over time scales too large to observe in the confines of an experiment, especially in vertebrates.  However, John Endler changed that idea with his work on guppies in the streams of Trinidad.  There, guppy coloration patterns are subject to sexual selection via mating preferences and natural selection via predation.  Along the streams, waterfalls divide different pools, and those pools have different levels of predation on guppies.  Endler took advantage of this natural experimental setup and transplanted guppies from higher predation pools to lower predation pools to test predictions about the evolution of their coloration under different selective regimes.  He was able to confirm his hypothesis that under lower predation, guppy coloration would evolve away from crypsis (advantageous under high predation) to more complex and colorful patterns (advantageous for mating).

Evolvability is Evolvable

It has long been theorized that organisms that can rapidly change to suit their environment would be favored over those who cannot. But is the ability to evolve itself selected for, or does evolvability arise due to other evolutionary processes? Researchers at the University of Pennsylvania studying lyme disease-causing bacteria Borrelia burgdorferi have studied the genetic makeup of bacteria one year after infection in mice and compared this to the original sample. They found that natural selection favors those cells that have more genetic variation in an unexpressed series of DNA "cassettes". These cassettes recombine with the coding sequence for the bacterial antigen to produce new forms that can evade the host immune system. Since the cassettes are not expressed, their variability should not be selected for unless they actually contribute to "evolvability".

The Genetics of Parasitism

When ruminating on the history of humanity one must also consider the blood-sucking louse, with which our destiny has been intertwined. This creature, bearing the smallest known insect genome, has associated with primates dating back at least 25 million years. Researchers at the J. Craig Venter Institute have sequenced and analyzed the body louse genome, as well as one of its obligate endosymbiont bacteria, finding that a great many genes found in the louse's free-living cousins have been lost, including those used for sensation in finding food and avoiding predation, and that the louse's own bacterial flora encode genes to synthesize nutrients not found in a blood diet. Together these findings provide a basis for the study of host-parasite evolution and could have important implications to our management of the louse as a vector for disease. 

The First Biological Gears Discovered!

Video (made into a GIF) from
the paper supplemental materials
There's been some talk about living organisms and the use of biological gears, and frankly, how there isn't any known in nature. They seem like a perfect system to move different things simultaneously, yet it looked like nothing had evolved it. Until a September 13th issue of Science, that is. Malcolm Burrows and Gregory Sutton wanted to know how planthopper nymphs were able to jump well and straight every time. They first looked at the back leg joints, and noted how synchronous the legs moved (and moved within 30 microseconds of each other!). Upon microscopy they noted the biological gears, and characterized the cocking and release mechanisms of the legs used to jump. Isn't nature awesome?!
Supplemental News Article with videos:

Creating the Pill (Nanoparticles) To Cure Drunkeness

What if you could one day control your drunkenness, just take a pill and be able to drive home a little later that night? A group in China is trying to make this a real possibility in the near future, using nanoparticles to help your body process alcohol many times faster than you normally could. The nanoparticles this group developed contain the three enzymes your body needs to process alcohol, so they are in close proximity to achieve the stepwise enzymatic activity needed by attaching these enzymes to one another using a DNA strand, before enclosing it in a nanoparticle “casing”. They’ve shown that this can and does work in mice, but unfortunately its product is the reason for hangovers so it’s not quite there yet. This does raise ethical questions though, on the ability to binge with no repercussions. What are your thoughts?

The Operon and Transcriptional Regulation
The ability of organisms to respond to a changing environment is fundamental for survival. One classically studied example of this type of response is bacteria's ability to process lactose when switched from a glucose to lactose containing media. In 1960, scientists knew lactose processing steps were accomplished by enzymes, but how these enzymes were regulated in response to lactose was poorly understood. Using transfer of sex factors to obtain diploid bacteria and bacteria with different enzyme/regulator mutations, Jacob and Monod discovered a mechanism for transcriptional regulation of these enzymes. Importantly, these experiments also led to the discovery of the operon, a unit of linked genes that can be coordinately regulated. This elegant mechanism of regulation allows multiple enzymes involved in the same pathway to be coordinately controlled. Since this study, transcriptional regulation has expanded into a huge area of study in many disciplines of biology.
A summary

Discovering Acetyl-CoA and the rest of the fatty acid cycle

Feodor Lynen
© Archive of the Max Planck Society,
 Dahlem, Berlin
Feodor Lynen, a German biochemist, devoted his career to researching metabolic processes. While studying with Heinrich Wieland, Lynen started looking into acetic acid metabolism. In yeast experiments they noted the Kreb's cycle did not explain all of metabolites found, and the conversion of acetic acid into citric acid was more complicated than originally thought. Lynen proposed that acetic acid was converted to an "activated acetic acid", but experiments couldn't prove he was right until after World War II when communication opened up between Germany and the rest of the world. Acetyl-coA had been discovered, but its isolation was impure and had a number of disulfide contaminants. Lynen was struck with the idea that acetyl-CoA was a thioester and went on to isolate and prove that this was the "activated acetic acid" he had proposed. Lynen determined the remainder of the fatty acid cycle and was rewarded with a Nobel prize.
Lynen's Nobel Lecture

The itsy-bitsy spider was all like "Mmmm. That looks yummy! I'm gonna ea-- OHMYGODLOLOLOZPLEASEDON'THURTME!!!"

Identifying traits that constitute adaptations has been a challenge for evolutionary biologists for over 150 years.  In recent memory, many biologists developed a habit of indiscriminately labeling virtually all traits as adaptations, often justifying the label with speculative "just-so stories" of adaptive utility.  This practice has been especially common in putative cases of Batesian mimicry, where even slight similarities of harmless organisms to dangerous organisms are assumed to be adaptive resemblances.  Greene et al. devised a simple but elegant experiment to test the hypothesis that a tephritid fly, Zonosemata vittigera, mimics the territorial displays of jumping spiders with its marked wings and elaborate wing display.  By replacing Z. vittigera wings with House Fly (Musca domestica) wings and vice versa, the team confirmed that both the wing waving behavior and the marked wings are necessary to deter predation by jumping spiders.

(Note: the video is of a different putative jumping spider mimic, Delphinia picta.  Courtesy of Ian Dworkin)
A similar study in Snowberry Flies

Zombie Ants

Running shoes, Check. Emergency stashes, Yep. Escape route, Planned.

You are zombie apocalypse ready, which is good because parasitic fungi that infect, behaviorally manipulate, and kill ants have recently been brought to the forefront of popular culture. (Could humans be next?)

Descriptive studies over the past several years paint a colorful picture of the life and death of Zombie Ants. Imagine: foraging ants encounter spores that adhere and penetrate their exoskeletons. Less than a week later, infected ants migrate up and clamp on to plant surfaces at precisely noon where they perish. The fungus then extends a stalk from the ant body releasing new spores on unsuspecting victims. 

Yet, the question remains, how do these different fungal species induce behavioral changes in their hosts? A recent paper offers insight using awesome ex vivo insect culture. The authors describe the metabolic changes induced by pathogen isolates in ant brain and muscle.

About the video: Sir David Attenborough brings you up close and personal with ants infected with Cordyceps.
Also of interest: Behavioral mechanisms and morphological symptoms of zombie ants dying from fungal infection.

Suspended animation: saving time on the way to deep space and the hospital

"Alien" (1979)
Suspended animation is a process where an organism’s physiological processes slow down to a point resembling death. Several species have been documented to undergo suspended animation during early development when in the complete absence of oxygen and/or freezing cold. Mimicking torpor and hibernation, animals under suspended animation display near halted metabolic rates with concomitant drop in heart rate, brain activity, and overall cellular activity. Upon re-exposure to oxygen and/or rewarming, physiological processes start up again and the organism lives out a normal lifespan. The applications for suspended animation in humans are far spanning from deep space exploration with living astronauts to saving the lives of victims of severe trauma. Furthermore, the means by which suspended animation can be induced with high survival rates during re-emergence is relatively simple and can be induced via several methods. In 2005, researchers in Seattle discovered the use of hydrogen sulfide gas in inducing suspended animation and were able to successfully place mice in near metabolic arrest for 6 hours with normal exit. This was the first time a mammal was successfully suspended and suggests it could be extended to humans.
  • The incredibly brief Science paper
A very recent and awesome paper on suspended animation

Experimental replication of a hybrid speciation event

Helianthus anomalus  (credit)
What makes a new species?  A difficult question, especially given the nature of the speciation continuum.  Loren Rieseberg and colleagues used a hybrid species complex, Helianthus annuus and H. petiolaris and their hybrid species, H. anomalus, to study the genetic architecture of hybrid species formation.  They experimentally generated hybrids of H. annuus and H. petiolaris and compared the genomes of those experimental hybrids to the ancient hybrid species, H. anomalus.  They found that the genome of the hybrid species is not a random mash-up of the parental genomes but instead is constrained by the interactions between the parental genes.  The hybridization event itself may have been a random occurrence, but the genetic composition of the resulting species was anything but random.

Evolving multicellularity in the lab

from Ratcliff et al., 2012
One of the biggest milestones in the evolution of the complex life that exists today was the formation of multicellular organisms. This major transition permitted an increase in the size of organisms as well as an opportunity for division of labor among cooperating cells. Using the unicellular yeast, S. cerevisiae, Ratcliff et al. selected for multicellularity by centrifugation. With this strategy larger yeast are more likely to be transferred to the next culture. Within 60 days yeast formed elaborate multicellular structures that produced multicellular progeny. The authors also observed a division of labor among cells. While early multicellular organisms were physiologically similar, later organisms showed an increase in programmed cell death. This experiment demonstrates the rapidity with which multicellular evolution can occur given the correct selective environment.
A news article explaining the findings

Silly science and frivolous funding: The history of statins

Akira Endo
Nature Medicine (2008)
Government funding of scientific research is often a targeted due to publicized ‘weird science.’ Yet, ‘weird scientists’ are behind several of the most important medical breakthroughs of our time! One such example include statins, a group of drugs commonly prescribed to treat high cholesterol. Over half of all American men and more than 2 in 5 American women over the age 65 take statins (National Center for Health Statistics, Health, United States, 2012).

Their unlikely origin: Fungi.

Dr. Akira Endo discovered the first statins in a screen searching for inhibitors of cholesterolgenesis from chemical compounds derived from Penicillium citrinum in the 1970s.  Three of the 6000 compounds tested reduced cholesterol synthesis in a rat liver enzyme model. (Talk about successful drug discovery!)  Today, statins remain the subject of ongoing research in the prevention of dementia, reduction of inflammation, and treatment of cancer and stroke.

An extra--Statins and diabetes risk: Risk of incident diabetes among patients treated with statins: population based study. 

An NPR report detailing a recent 'weird science' controversy (worth a listen!):  'Shrimp On A Treadmill': The Politics Of 'Silly' Studies

Why do grasshopper mice feel no pain when stung by bark scorpions?

Pain is an adaptive trait that warns of tissue damage for the survival purpose. Reduce of pain sensitivity may put animals in danger of injury and death from environmental threats. However, there is an exception--- desert-dwelling grasshopper mice have evolved resistance to the pain-inducing venom from its prey, bark scorpions. What is the molecular mechanism underlying this pain resistance? It turns out that the pain-transmitting sodium channel of grasshopper mice, Nav1.8, has few amino acid different from other mammals. Therefore, rather than blocking the binding of bark scorpion toxins, the amino acid variants promotes the venom binding and inhibit Na+ current to block the transmission of the pain signals. This finding shed the new light on analgesic therapy.

A review about different types of sodium channel in pain

Stay calm: Stress fuels cancer metastasis


It has been noticed that breast cancer patients who suffer from stress and depression following the primary treatment tend to have higher rates of relapse, metastasis and death. Even though this observation has been confirmed in mice, the mechanistic link between stress and metastasis is still unknown. Campbell et al. beautifully put the whole picture together. They proved that stimulation of the sympathetic nervous system in mice, a consequence of chronic stress and depression, promotes breast cancer cells to metastasize to bone by changing the bone marrow microenvironment. Under stress condition, the level of cytokine RANKL is increased in host bone marrow stroma, which enhances bone breakdown and makes the colonization of breast cancer cells in bone easier. Most importantly, the metastasis can be reduced by blocking the effects of stress, suggesting a new therapeutic strategy to prevent breast cancer metastasis–reducing stress in patients. 
Extra: Is living better equal to living longer?

Sexual Isolation in Drosophila

A thriving area of research at present concerns the genetic basis of speciation.  Popular topics include the hunt for genes that consistently are involved in speciation in a variety of taxa, the genetics of postzygotic isolation, and whether many genes with small effects or few genes with large effects are more important in the process of divergence.  Even as recent as the 90s, little had been done on the genetics of speciation.  In 1994, Jerry Coyne and colleagues designed a simple but brilliant experiment to demonstrate that species-specific pheromones (cuticular hydrocarbons) are involved in sexual isolation between two sister taxa, Drosophila sechellia and D. simulans.  After identifying a role for pheromones in species recognition, the authors used a clever mapping technique to identify the genetic basis of the key pheromonal differences.  This study provided some of the first evidence that key trait differences between species may be based on a few genes with large effect sizes.

(Video credit: ClyneFlicks on Youtube)
One of the most important speciation papers. Ever.

To necrose or simply apoptose

 Endochondral ossification of developing vertebrae.
University of New South Wales, Cell Biology.
The term ‘cycle of life’ elicits imaginings of birth, growth and development, reproduction, and of eventual death. Yet, the ‘cell cycle’ is a term used to typically only refer to the process of cellular division and replication.  In fact, programmed cell death was first described even before the process of cellular division. In 1842, Karl Vogt noticed that the notochord of the midwife toad was replaced by vertebrae during development and suggested this was due to cellular reabsorption followed by replacement by nearby cartilage cells.  His research, which set the foundation for the field of apoptosis, was not followed up until much later.  In the century following, most research focused on bone ossification or the cellular death that occurs in metamorphic insects and amphibians during maturation (for example, loss of the tadpole tail and gills, and the changes that occur in flies during pupation). Unfortunately, most of this early research was all published in French and German, and therefore inaccessible for this platform. However in the field of apoptosis, another integral work published in 1965 by John Kerr distinguishes programmed cell death and traumatic cellular death. Kerr described unique histological changes in rat liver after portal vein ligation injury, which he called ‘shrinkage necrosis’ before later coining the term ‘apoptosis.’

This seems long, but as most of it is histology images it is a fairly quick read:

An interesting history summarizing early apoptosis research that I found useful:
P.G. Clarke & S. Clarke (2012). "Nineteenth century research on cell death." Exp. Oncol., 34: 139-145.

For the polyglot: K.C. Vogt (1842). "Untersuchungen über die Entwicklungsgeschichte der Geburtshelferkröte (Alytes obstetricans)." Solothurn: Jent und Gassmann.

Test tube babies and octomom: Development of in vitro fertilization

Photo credit
Infertility can be a major psychological stress in couples who desire to have children, and it affects approximately 3-10% of couples worldwide. However, in 1978 Robert Edwards helped pioneer a way to combat fertility issues through the development of in vitro fertilization (IVF). This technique involves the implantation of a human embryo fertilized outside of woman’s body into her uterus. The first “test tube baby,” Louise Brown, has since had a child of her own, and Robert Edwards received the Nobel Prize in Medicine in 2010. This misuse of technique has also created some controversy in recent years when Natalie Suleman (also known as “Octomom”) gave birth to octuplets in January 2009.
Use of IVF to allow those with Klinefelter's Syndrome to have children

Traveling through time: The generation of iPS cells

iPS Cell Research & Challenges It Faces
The pluripotent nature of embryonic stem cells (ESCs) offers the ability to regenerate a vast array of cell types that may otherwise be challenging to acquire. However, obtaining human ESCs brings with it a host of concerns, including political and ethical challenges. Because of the promising potential of ESCs, Takahashi and Yamanaka, sought a method of generating ES-like cells, termed induced pluripotent stem (iPS) cells. They identified four factors (Oct3/4, Sox2, c-Myc, Klf4) necessary and sufficient to reprogram somatic cells back to their pluripotent state. This discovery opened the doors for regenerative therapies by offering the potential to regenerate any cell type from an individual’s own somatic cells, thus potentially eliminating host rejection. In just seven years since its publication, the Takahashi and Yamanaka paper has begun to revolutionize stem cell biology.
NYT on Yamanaka: Cloning and Stem Cell Work Earns Nobel 
Photo: Shinya Yamanaka, Nobel Prize winner in 2012 "for the discovery that mature cells can be reprogrammed to become pluripotent". Photo Credit

Studying the cell cycle, without the cell!

The 2001 Nobel Prize in Medicine went to Lee Hartwell, Tim Hunt, and Paul Nurse for their elucidation of the mechanisms underlying cell cycle control. It may be surprising, then, that many of the studies that led to these discoveries were performed in the absence of cells. Such a study was performed in this 1987 study by Christopher Hutchison and colleagues, using cell free extracts of Xenopus eggs. Incredibly, these cytoplasmic extracts were able to generate pronuclei derived from sperm heads, allowing researchers to employ pulse and continuous labelling to examine DNA synthesis. By performing these experiments in the presence and absence of a protein synthesis inhibitor, the authors of this study were able to determine that DNA synthesis is cyclic, thus laying the foundation for some of Tim Hunt’s work. 

Our understanding of the cell cycle in 1989 (Murray and Kirschner, 1989)
Building on this, Tim Hunt's group used cell-free extracts to show that transcription of cyclins were necessary for entry into mitosis. All of this is summarised in this 1989 review by Andrew Murray and Marc Kirschner.

Organising the embryo

From DeRobertis, 2006
How does a fertilised egg develop into a complex organism with trillions of cells? It is a question that has plagued generations of developmental biologists. At the turn of the 20th century, Hans Spemann and his graduate student Hilde Mangold performed one of the seminal experiments in developmental biology. The pair performed “cut-and-paste” experiments that elucidated the organising function of the upper blastopore lip of the gastrulating embryo. While this was not the first example of such an experiment, its use of the two salamander species with different pigmentation patterns allowed scientists to determine the contribution of explants to different embryos. Despite their primitive means (Spemann allegedly chased young boys around town to find hair fine enough to divide the developing embryos), the results and conclusions of Mangold and Spemann have formed the backbone of developmental biology for close to a century.
  • The original paper (as were most scientific papers at the time) was published in German, and is (perhaps by necessity) quite long. A translation is found here

How Mosquitoes Survive Rainstorms

Mosquito and a raindrop - an image
from the paper
Ever wonder how mosquitoes (or other small insects) survive through a rainstorm, where a raindrop weighs 50 times more than them? Probably not, but you’re probably wondering now! Good thing a group of scientists in Atlanta have recently answered this paradox, and unfortunately it’s not dodging them like the matrix. The key to its success is its small mass. After lots of aiming raindrops at mosquitoes and some high-tech videography, they watched what happened to the mosquitoes after they were hit. They find that due to their small mass, the raindrop lost little momentum and imparted little force on the mosquito. It’s as if they didn’t even feel it…
Video of the in-flight collisions:

R loops found within DNA-RNA hybrids - The Intronic Story

The famous R-loop picture from the paper
Wouldn’t life be simpler if DNA just coded RNA which just coded protein? That’s how we used to think, but unfortunately we all know that RNA isn’t so simple. We now know that genes contain both introns and exons, and the introns have to (all or selected ones) be spliced out. The discovery of introns first came from Dr. Phillip Sharp, who wanted to better understand how viral mRNA can be selectively taken out of the nucleus opposed to other. Coupled with his knowledge of mRNA processing that occurs, he made a viral ssDNA-RNA hybrid and viewed it under the microscope. There he viewed R loops, or loops that ssDNA made where it had no matching RNA partner. He concluded that these must’ve been areas of DNA that got spliced out when making mRNA, giving us the concept of introns.
Additional Nobel Prize winning paper:

New insight into tissue regenerative potential in mammals

Star Wars Episode V: The Empire Strikes Back (1980)
Tissue regeneration is not known to occur in mammals. Instead, we have evolved repair mechanisms that aim to rebuild damaged structures to near-original states. Though this strategy is more cost effective with regard to cellular energy and time, it does not provide the plasticity required to fully regenerate loss appendages (e.g. Luke's hand) or organs. People have been studying regeneration for decades and have relied predominantly on non-mammalian models such as crustaceans, amphibians, and insects, all of which show remarkable capacities for regeneration. Recently, a group at the University of Florida reported the first known case of complete regeneration within a mammal that undergoes autotomy - otherwise known as “self amputation”. Their findings underscore the important yet unknown role of the highly conserved regenerative structure known as the “blastema” and pose several exciting questions regarding tissue regenerative potential in mammals.

Fathers of stem cell research

Ernest McCulloch and James Till
Stem cells have the ability of cell-renewal and differentiation into other cell types. The magic of stem cells brings new hope to patients, leading to all kinds of possibilities for therapeutic use. Bone marrow transplantation serves as a great example, which has been extensively used to treat Leukemia. Aren’t you curious about “when” and “how” stem cells were firstly identified? Back to 1960s, scientists tried to find ways to treat people who exposed to radiation during nuclear war. Ernest McCulloch and James Till started to give mice high doses of radiation and then injected bone marrow cells into those irradiated mice. They found that the number of injected cells is correlated with the survival rate and the number of clones formed in the spleen. Ernest and James are the first to prove the existence of stem cells and further characterized them.

A short review by Ernest McCulloch and James Till

CRISPR-The coolest new tool for your scientific toolbox (discussed by the group on Nov 13, 2013)

No, I'm not talking about the bottom drawer of your fridge, but instead about the new genomic engineering tool. The CRISPR/cas system provides an adaptive immunity against plasmids and phages in bacteria and archaea. While this adaptive immunity is great for the microbiologists in the yogurt industry, why should CRISPR be put into your molecular biology toolbox? With target specific crRNA and the Cas9 protein, a specific DNA sequence or gene can be completely excised or just replaced with DNA of your own design into seemingly any model organism of your choice. The CRISPR targeting system has exploded this year and many different groups have used it to modify genes in human cells, mice, rats, zebrafish, bacteria, fruit flies, yeast, nematodes, rice and wheat. One group has even generated knockout mice using this system!
Additional Reading: The CRISPR Craze - Science 2013 and Heritable gene targeting in the mouse and rat using CRISPR-Cas system- Nature Biotechnology 2013

Video: The CRISPR Song from iGEM-Freiberg via YouTube.

The Birth of Gel Electrophoresis

The father of electrophoresis is considered to be Arne Tiselius who, in the 1930s, invented the U-shaped Tiselius apparatus used for separation of molecules by an applied electric current. Although generally effective, the Tiselius method had some major drawbacks as to the amount of protein sample needed, contamination, and incomplete separation of polypeptides. Tiselius later invented a better method of electrophoresis using filter paper, but the proteins often stuck to the paper and "unrolled" themselves. However, in the 1950s, UNC's own Oliver Smithies invented the gel electrophoresis after reminiscing about helping his mother do the laundry as a child. He remembered how the starch concoction his mother used to starch the collars of his father's shirts would turn into a jelly when left sitting out. He postulated that he could make a starch gel in which the proteins could travel and separate, and be observed by applying a stain. Today, gel electrophoresis is widely used in laboratories, and taught in schools around the world.
Zone Electrophoresis in Starch Gels
How It All Began: a Personal History of Gel Electrophoresis written by Oliver Smithies (contains pictures from his original lab notebooks, including the one pictured above)

Packaging DNA

Electron micrograph of chromatin
demonstrating "beads on a string" (credit)
There are approximately 6 billion base pairs of DNA that make up a diploid human genome. This stretches to over 2 meters of DNA that must fit into a single cell. During the 1900s many scientists sought to uncover how DNA packaged into a single cell through x-ray diffraction studies. However, it wasn't until 1974 when Olins used electron microscopy to demonstrate the packaged nature of chromatin as beads on a string. This provided the first evidence that nucleosomes existed. A year later in 1975, Thomas and Kornberg demonstrated that repeating histone octamers comprised of H2A, H2B, H3 and H4 were present throughout a chromatin fiber and could be a means of further packaging DNA. Together these papers laid the foundational work for how DNA is packaged. 
Extra: Thomas and Kornberg


The creation of PCR revolutionized science. It changed the way we think about studying genetics and made studying genes much easier, not to mention cheaper. Kary Mullis was working as a chemist for Cetus when he came up with the idea to use DNA primers to bracket a region of interest in the genome and amplify it using DNA polymerase. Mullis and his coworkers were the first to optimize PCR and use it to amplify regions of the genome. PCR has since become a mundane task that infiltrates thousands of labs. Mullis received a $10,000 bonus from Cetus and the 1993 Nobel Prize for this discovery.
Extra: Mullis' description of PCR, ironically published after the paper above.

Video from BioRad via YouTube.

Fibroblasts May Cause Cancer Metastasis

Fibroblasts are the cells in the body that are supposed to maintain the structure of the extracellular matrix by making proteins that are precursors of the components of the matrix. They are usually mentioned in the same breath as wound healing, and tissue repair. However, studies have recently shown that there are fibroblasts that have been associated with tumor cell metastasis. In this paper, Gaggioli et al have shown in a series of experiments that tumor-associated fibroblasts not only promote metastasis of cancer cells, but actually pave the way by creating tracks in the extracellular matrix. Their analysis of clinical samples revealed that a similar phenomena occurs in vivo. The group found that the fibroblasts utilize Rho and ROCK to contract and tear holes in the matrix as they travel along, thereby leaving a trail for the cancer cells to follow.
Review on Fibroblasts in Cancer

It's electric...

Borgens et al., 1981
The idea of living biological systems possessing electrical properties has been known for well over two centuries. To most biologists, the though of electrically excitable cells such as neurons and muscle first come to mind but what else is electrical about living systems and is this property truly important beyond an organisms ability to perceive and respond to the outside world? Original works on the subject of "bioelectricity" can be dated back to the physicist, Luigi Galvani, who in the mid-18th century performed the spectacular but controversial experiment where frog legs were made to twitch upon application of electricity. This seemingly convincing reanimation of life with electricity was at the time greatly refuted and to some extent shown to be artifactual by the prominent physicist, Alessandro Volta (think inventor of battery and major contributor to our current understanding of electricity). Strangely, it wasn't really until about 30 years ago that a handful of people began looking back into bioelectricity and its endogenous roles in physiology and perhaps more interestingly, its therapeutic potential in medicine. Since then, electric fields have been shown to be involved in a myriad of events in an organisms life but how it works is still completely unknown and still controversial.

There are several possible directions to go with this subject but I think a good one to look at is a somewhat seminal and relatively straightforward study where application of electric fields was shown to enhance spinal repair.

After 40 years the mysterious function of telomeres was solved

Telomeres (yellow), used with permission
The scientific community knew about telomeres for ~40 years before its role of chromosome protection was determined by Blackburn and Szostak. In the 1930s, both Muller, who gave telomeres their name, and McClintock hypothesized that telomeres protect chromosomes, but without the appropriate molecular techniques the field lost interest. Blackburn, who had found short repeating DNA in telomeres, presented her data at a conference in 1980. Szostak was working with linear DNA or "minichromosomes" in yeast that degraded rapidly, and after hearing Blackburn's research became interested in collaborating. In a simple experiment, they attached Blackburn's telomeric DNA to Szostak's minichromosomes and were excited when they noticed the minichromosomes were protected from degradation. Blackburn and her graduate student Greider went on to discover telomerase and ultimately earned all three the Nobel Prize in 2009. Learning the function of telomeres and how they are synthesized has opened the doors to aging and cancer research.
An optional article about Blackburn: Natural History Blackburn article

The dangers of double-dipping

image credit
Have you ever been making your way to the snack table for a plate of chips and dip, when you see someone dipping a half-eaten chip back into the onion dip? Hopefully, witnessing such a social blunder deters you from partaking from the communal dip. If not, scientist Paul Dawson from Clemson University has conducted a study that should convince you to steer clear of the dip that's been double-dipped. After being inspired by an episode of "Seinfeld," Dawson conducted a study on the spread of oral bacteria caused by double-dipping crackers or chips into salsa, chocolate sauce and cheese. His study not only shows that double-dipping causes bacterial contamination, but supports implications of the spread of disease from contaminated party snacks.
Paul Dawson's public service announcement on the "Five-Second Rule"
The Seinfeld clip of the Chip Dip that inspired Dawson

Glowing in a sea of darkness (discussed by the group on 10/23/13)

An image of the brain stem whereby different
structures are expressing different fluorescent
proteins to demonstrate the formation of
synapses between axons and neurons.  Photo Credit
The 20th century marked a vast development in the fields of genetics and biochemistry. During this time the structure of DNA was uncovered, enzyme function could be assessed through crystallography and NMR, and whole genome sequencing was being developed. With these advancements, however, there was still no mode of tracking the location of proteins or monitoring the cellular processes of proteins in a living system. The discovery of the green fluorescent protein (GFP), however, opened the doors for monitoring and viewing proteins in a cell. Osamu Shimomura first identified GFP in 1962 when he isolated the bioluminescent protein from the jellyfish, Aequorea victoria. It wasn't until 1994, however, when Martin Chalfie demonstrated the utility of GFP as a fluorescent marker. This discovery would later earn him a Nobel Prize alongside Shimomura. The ubiquitous use of fluorescent proteins in laboratories worldwide undoubtedly demonstrates the impact of this discovery.

Darwin's "warm little pond": the Miller-Urey experiment (discussed by the group on 10/9/13)

The scientific community’s eventual acceptance of natural selection as the driver of diversity of life-forms opened many lines of inquiry, including the origin of life and how complex organic molecules required for life could possibly form from simpler inorganic chemicals. Darwin himself spoke to friends of a hypothetical primordial soup where this might occur.

In 1953 at the University of Chicago, Stanley Miller and Harold Urey placed several gases (methane, ammonia, and hydrogen) into a closed system with heated water and an electrical spark to simulate lightning storms, conditions thought to be present in early Earth’s atmosphere. Within weeks, >10% of carbon in the experiment was found in the form of organic compounds including amino acids, the building block of proteins. Subsequent experiments have shown that nucleotide bases can also be formed in such conditions, such as adenosine, also the key component of ATP. The original experiment continues today at the University of California San Diego, and its findings have guided the field of abiogenesis, an investigation that’s since been extended to include extraterrestrial sources.
Q: Are ancestral gene products enriched for Miller-Urey amino acids?
A: Yes, yes they are

The microbiome, the human genome, and diet: An emerging story of symbiosis (discussed by the group on 10/16/13)

You are what you eat. You also happen to be what the thousands of other microbes that inhabit your body eat.  Far more important than either one alone is the relationship between you, your microbiome, and your diet, which together influence your risk for certain diseases.  

A recent paper by Wang et al. (2011) is one of the first to show the effects of imbalance in this complex dance resulting in disease risk. Through a metabolomic screen, the formation of atherosclerotic plaques was found to be associated with a metabolite, whose generation requires certain intestinal microbes, a human protein in the liver, and dietary sources of choline such as fish, red meat, eggs, and milk.  The relationship between host genetics, the microbiome, and environmental factors, is emerging as an exciting area of focus in understanding the architecture of complex disease.

The Paper:
See also: Tang, W.H.W. et al. New England Journal of Medicine 368, 1575-1584 (2013).

A schematic showing the three components necessary for TMAO production. Wang et al. (2011) showed that TMAO is highly associated with cardiovascular disease risk. Figure from Rak & Radar, Nature, 472, 40-41 (2011).

Lords of the flies

Drosophila melanogaster
by André Karwath
“Let’s do a screen.” It’s a phrase bandied about in laboratories all over the world from scientists at all stages of their careers. However, the power of genetic screens was not fully realised until the late 1970s, when Christiane Nüsslein-Volhard and Eric Wieschaus performed their famous screen that identified mutations affecting Drosophila developmental patterning.

The first results of the Nüsslein-Volhard and Weischaus screens were published in a Nature paper in late 1980. Despite having incomplete results, the work presented is remarkable in that it identified and categorised a majority of the segmentation patterning genes in Drosophila. In designating different levels of organisation in the developing embryo, this screen helped elucidate our current understanding of development. While it certainly wasn’t the first screen, its scale and breadth laid the groundwork for not only future studies in Drosophila and other models, but arguably started the field of developmental genetics.

In 1984, Nüsslein-Volhard, Wieschaus, and colleagues published the complete results of their screen. These were published in a total of three papers, one for the 2nd chromosome, one for the 3rd, and one for X and the 4th chromosome (the latter of which is vestigial in flies).

Some historical perspective from Wolfgang Driever (a graduate student of CNV) and Janni Nüsslein-Volhard herself